title: Pharmacodynamic and pharmacokinetic profile of RBx 343E48F0: a novel, long acting muscarinic receptor antagonist.
abstract: RBx 343E48F0 is a novel, potent, selective and long acting muscarinic receptor antagonist with a potential for use in the treatment of Chronic Obstructive Pulmonary Disease (COPD). The aim of the present study was to describe the in vitro and in vivo profile of RBx 343E48F0 and to compare the results with the present day benchmark therapy, tiotropium. Radioligand binding and isolated tissue based functional assays were used to evaluate the affinity, potency and receptor subtype selectivity of RBx 343E48F0. Inhibition of carbachol-induced bronchoconstriction in the anaesthetized rat and acetylcholine-induced bronchoconstriction in the conscious rat were used to assess the extent and duration of the bronchospasmolytic activity of RBx 343E48F0. In vitro and in vivo pharmacokinetic studies were conducted to evaluate the pharmacokinetic and lung retention properties of the compound. In vitro radioligand binding studies using human recombinant muscarinic receptors showed that RBx 343E48F0 had a pKi of 9.6 at the M(3) receptor and a 60-fold selectivity for the M(3) receptor over the M(2) receptor. In isolated tissue bioassays, it exhibited surmountable antagonism at the guinea pig trachea with a pK(B) of 9.5. Intratracheal administration to anaesthetized rats demonstrated a dose-dependent inhibition of carbachol-induced bronchoconstriction with an ED(50) value of 110 ng/kg. RBx 343E48F0 also exhibited a fast onset of action and long duration of action of greater 24h.
authors.affiliation: Ranbaxy Research Laboratories Limited, Gurgaon, India. suman.gupta.mm@dsin.co.in
authors.forename: Suman
authors.initials: S
authors.lastname: Gupta
authors.forename: Shivani
authors.initials: S
authors.lastname: Malhotra
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sinha
authors.forename: Shashi K
authors.initials: SK
authors.lastname: Singh
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Siddarangaiah
authors.initials: S
authors.lastname: Krishna
authors.forename: Pooja
authors.initials: P
authors.lastname: Chhabra
authors.forename: Tridib
authors.initials: T
authors.lastname: Chaira
authors.forename: Janaki
authors.initials: J
authors.lastname: Kannayiram
authors.forename: Pradeep
authors.initials: P
authors.lastname: Sharma
authors.forename: Shelly
authors.initials: S
authors.lastname: Aeron
authors.forename: Jaskiran
authors.initials: J
authors.lastname: Kaur
authors.forename: Naresh
authors.initials: N
authors.lastname: Kumar
authors.forename: Jitendra
authors.initials: J
authors.lastname: Sattigeri
authors.forename: Raj K
authors.initials: RK
authors.lastname: Shirumalla
authors.forename: Jyoti
authors.initials: J
authors.lastname: Paliwal
authors.forename: Sunanda G
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Ian A
authors.initials: IA
authors.lastname: Cliffe
authors.forename: Abhijit
authors.initials: A
authors.lastname: Ray
authors.forename: Pradip
authors.initials: P
authors.lastname: Bhatnagar
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016210:Methacholine Chloride / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012121:Respiration, Artificial; D013379:Substrate Specificity
chemical_list: D007093:Imidazoles; D018727:Muscarinic Antagonists; C559682:RBx 343E48F0; D011976:Receptors, Muscarinic; D016210:Methacholine Chloride; D000109:Acetylcholine